“Allergic rhinitis” refers to a symptomatic disorder of the nose induced by an IgE-mediated inflammation after allergen exposure of the membrane of the nose. The allergic rhinitis includes such symptoms as rhinorrhea, nasal obstruction, nasal itching, sneezing, ocular pruritis and so on.
“Asthma” refers to a disorder wherein inflammation of the airways causes bronchial mucosa to swell and muscular convulsion to occur in bronchi which restricts airflow into and out of the lungs. Asthma may cause such symptoms as shortness of breath, severe coughing, and in severe cases, status asthmaticus, which may result in even death.
Allergic rhinitis and asthma may develop separately; however, there is a study showing that approximately 58% of patients with allergic rhinitis have asthma as well and that 85˜95% of patients with asthma also suffer from allergic rhinitis, indicating high rates of complications between said two patient groups. Thus, there has been a need for developing a combination composition, which has an improved stability and efficacy for treatment of said two conditions.
Meanwhile, Cetirizine is (2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)acetic acid, and its levorotatory and dextrorotatory enantiomers were disclosed as “Levocetirizine” and “Dextrocetirizine”, respectively.
Levocetirizine can be obtained by separation from a racemic mixture of Cetirizine or asymmetric synthesis, e.g., conventional methods disclosed in UK Patent No. 2225321, or enzymatic biocatalytic hydrolysis disclosed in U.S. Pat. Nos. 4,800,162 and 5,057,427. Levocetirizine possesses antihistamine properties and hence is useful as an antiallergenic and an antihistamine agent, as well as an anticonvulsant and a bronchodilator. Also, levocetirizine dihydrochloride is approved for treating allergic rhinitis and sold under Xyzal (Yuhan Corporation).
Montelukast is an antagonist inhibiting cysteinyl leukotriene type 1 (CysLT1) receptor, which is used for prevention and treatment of leukotriene-mediated diseases. Particularly, it has been reported that montelukast is effective in the treatment of allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyp, chronic obstructive pulmonary disease, conjunctivitis including nasal conjunctivitis, migraine, cystic fibrosis, viral bronchiolitis, and the like [see, e.g., S. E. Dahlen, Eur. J. Pharmacol., 533(1-3), 40-56(2006)]. Further, Singulair (MSD) comprising montelukast sodium is approved for treating asthma in adults and pediatric patients of 2 years plus, and currently available in the market.
There has been a report relating to a pharmaceutical composition in a bilayer tablet form comprising montelukast sodium, which is stable in a basic condition, and levocetirizine dihydrochloride, which is stable in an acidic condition [R. T. Rathod, J. Indian Med. Assoc., 107(8), 562-564(2009)]. In the preparation of said composition in a tablet form, it is very difficult to completely separate montelukast and levocetirizine from each other. Even in case a bilayer tablet is formed, it is impossible to mechanically separate each active ingredient completely. Moreover, a bilayer tablet machine is required in order to manufacture such tablets.
In addition, Levocetirizine is also unstable in terms of physiochemical properties, and it is difficult to prepare a stable product against aging. There are three major degradation products of Levocetirizine, which include related substance A of formula (I), related substance B of formula (II), and related substance F of formula (III). Related substances A and B are produced via hydrolysis of Levocetirizine, and related substance F is created via side reaction of Levocetirizine with excipients or releasing agents of hard capsule. In fact, Levocetirizine shows an increased rate of formation of related substances A, B, and F under accelerated storage conditions, and hence it is not easy to provide stability during the manufacturing process of capsule formulation.

Montelukast is known to be unstable when exposed to light, heat, or moisture, and yields such degraded products as montelukast sulfoxide of formula (IV) and montelukast cis-isomer of formula (V). According to a reference [see M. M. Al Omani et al., J. Pharm. and Biomed. Anal., 45, 465-471(2007)], when a commercially available Singulair chewable tablet was exposed to sunlight, the amount of montelukast sulfoxide was increased by 2.4% after 3 weeks; and when montelukast in 0.1 M hydrochloric acid solution was exposed to sodium light for 6 hours, the amount of montelukast cis-isomer was increased by 14.6%. As shown in the report, it is not easy to prepare a stable montelukast product against aging.

During the manufacturing process of hard capsule, capsule materials and excipients are employed so as to maintain the capsule shape and make the capsule surface smooth. Examples of capsule materials include gelatin, pullulan, hypromellose, polyvinyl alcohol and the like; and examples of excipients include diacetylated monoglyceride, sucrose fatty acid ester, sodium lauryl sulfate and the like. Also, a release agent such as mineral oil, lecithin and the like is used for release of capsules easily from the mold which forms the shape of the capsule.
The present inventors have conducted a research on a combination formulation comprising levocetirizine or a pharmaceutically acceptable salt thereof and montelukast or a pharmaceutically acceptable salt thereof as active ingredients. They have discovered that when levocetirizine and montelukast were prepared in separate tablets and then filled in a hard capsule, the amount of related substances increased more rapidly as compared to the composition in the form of single-active ingredient tablets due to materials derived from excipients and release agents as well as the moisture content existing in the capsule, and hence stability of active ingredients is deteriorated. Therefore, the present inventors have endeavored to resolve the problem and have found that the production of levocetirizine and montelukast related substances can be effectively inhibited when an organic acid such as citric acid is employed in a particle part comprising levocetirizine, and thus, have good long-term storage stability, even after the active ingredients were filled in a hard capsule.